WO2004011446A1 - Derives d'acide carboxylique d'indane, de dihydrobenzofurane et de tetrahydronaphthalene et leurs utilisations comme antidiabetiques - Google Patents

Derives d'acide carboxylique d'indane, de dihydrobenzofurane et de tetrahydronaphthalene et leurs utilisations comme antidiabetiques Download PDF

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WO2004011446A1
WO2004011446A1 PCT/US2003/023342 US0323342W WO2004011446A1 WO 2004011446 A1 WO2004011446 A1 WO 2004011446A1 US 0323342 W US0323342 W US 0323342W WO 2004011446 A1 WO2004011446 A1 WO 2004011446A1
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alkyl
phenyl
optionally substituted
mmol
alkoxy
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PCT/US2003/023342
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Philip Wickens
Louis-David Cantin
Chih-Yuan Chuang
Miao Dai
Martin F. Hentemann
Ellalahewage Kumarasinghe
Sidney X. Liang
Derek B. Lowe
Tatiana E. Shelekhin
Yamin Wang
Chengzhi Zhang
Hai-Jun Zhang
Qian Zhao
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Bayer Pharmaceuticals Corporation
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Priority to AU2003263814A priority Critical patent/AU2003263814A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07—ORGANIC CHEMISTRY
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/68—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention is directed to the use of indane, dihydrobenzofuran, and tetrahydronaphthalene carboxylic acid derivatives and pharmaceutical compositions useful in the treatment of diseases such as diabetes, obesity, hyperlipidemia, and atherosclerotic disease.
  • the invention is also directed to intermediates useful in preparation of said carboxylic derivatives and to methods of preparation.
  • Atherosclerotic disease is known to be caused by a number of factors, for example, hypertension, diabetes, low levels of high-density lipoprotein (HDL), and high levels of low-density lipoprotein (LDL).
  • Atherosclerotic diseases include cardiovascular disease, coronary heart disease (CHD), cerebrovascular disease, and peripheral vessel disease.
  • Coronary heart disease includes CHD death, myocardial infarction, and coronary revascularization.
  • Cerebrovascular disease includes ischemic or hemorrhagic stroke, and transient ischemic attacks.
  • the present invention relates to compounds which are useful in the treatment of diabetes and related disorders such as Syndrome X, impaired glucose tolerance, impaired fasting glucose, and hyperinsulinemia; obesity; atherosclerotic disease and related disorders such as hypertriglyceridemia and hypercholesteremia; cardiovascular disease, and cerebrovascular disease.
  • diabetes and related disorders such as Syndrome X, impaired glucose tolerance, impaired fasting glucose, and hyperinsulinemia; obesity; atherosclerotic disease and related disorders such as hypertriglyceridemia and hypercholesteremia; cardiovascular disease, and cerebrovascular disease.
  • the present invention encompasses the compounds of Formulae (la)-(le),
  • R 2 is H, F, or (C C 6 )alkyl;
  • R 3 is H, F, or (C C 6 )alkyl;
  • R 4 is H or (CrC ⁇ )alkyl;
  • R 5 is H or (C C 6 )alkyl;
  • R 6 is H or (C C 6 )alkyl;
  • R 7 is H, (CrC 6 )alkoxy, OH, O-SO 2 CF 3 , halo, 1 ,3-benzodioxolyl, or phenyl optionally substituted with one or more (C C 6 )alkyl or (CrC 6 )aIkoxy;
  • R 9 is H,
  • R 14 is H
  • R 18 is H or F;
  • R 19 is H, CI, or Br;
  • R 20 is (C C 6 )alkyl or phenyl optionally substituted by CO 2 H, (C C 3 )alkyl, (C C 6 )alkoxy, or CF 3 ;
  • R 21 is H, halo, (C C 6 )alkyl, 1 ,3-benzodioxolyl, phenyl, wherein said phenyl is optionally substituted with one or more CO 2 H, halo, (C C 6 )alkyl, CF 3 , or (C-rC 6 )alkoxy;
  • R 22 is (C C 6 )alkoxy, (C C 3 )alkyl, or CF 3 ;
  • n 1 or 3;
  • R 2 and R 3 are (C C 6 )alkyl; .
  • R 4 is (C C 6 )alkyl;
  • R 10 is O-SO 2 CF 3 , 1,3-benzodioxolyl, or phenyl optionally substituted with one or more (C C 6 )alkyl, halo, (C C 6 )alkoxy, (CrC 6 )alkylthio, or CF 3 ;
  • R 7 is attached at the 5 position of the indane ring
  • (C C 3 )alkyl mean linear or branched saturated carbon groups having from about 1 to about 3, about 4, or about 6 C atoms, respectively. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.
  • (C 2 -C 4 )alkenyl means a linear or branched unsaturated carbon group having from about 2 to about 4 C atoms in which a double bond is present between any two available carbons in the group and includes such groups as 1-ethenyl, 2-propenyl, isopropenyl, 2-methyl-2-propenyl, 2-butenyl, 3-butenyl, and the like.
  • (C C 3 )alkoxy means a linear or branched saturated carbon group having from about 1 to about 3, about 4, or about 6 C atoms, respectively, said carbon group being attached to an O atom.
  • the O atom is the point of attachment of the alkoxy substituent to the rest of the molecule.
  • Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • (C C 3 )alkylthio and “(C-i-C 6 )alkylthio” means a linear or branched saturated carbon group having from about 1 to about 3 C atoms or about 6 C atoms, said carbon group being attached to an S atom.
  • the S atom is the point of attachment of the alkylthio substituent to the rest of the molecule.
  • Such groups include but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like.
  • a phenyl ring or a heterocycle is attached to the rest of the molecule, it is attached by replacing any H atom on the phenyl ring or on the heterocycle, respectively, with a bond to the rest of the molecule.
  • the substituent(s) may be attached to the phenyl ring at any available C atom.
  • each substituent is selected independently from the other so that they may be the same or different.
  • a salt of a compound of Formulae (la)-(le) may be prepared in situ during the final isolation and purification of a compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • a salt of said compound of Formulae (la)-(le) may be prepared by separately reacting it with a suitable inorganic or organic base and isolating the salt thus formed.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention (see, e.g., Berge et al., J. Pharm. Sci. 66:1-19, 1977).
  • Representative salts of the compounds of Formulae (la)-(le) include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mande
  • Base salts include, for example, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.
  • basic nitrogen containing groups in the conjugate base may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides; aralkyl halides like benzyl and phenethyl bromides, and the like.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as de
  • esters of Formulae (la)-(le) in the present invention are non-toxic, pharmaceutically acceptable esters, for example, alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or pentyl esters. Additional esters such as, for example, methyl ester or phenyl-C 1 -C 5 alkyl may be used.
  • the compound of Formulae (la)-(le) may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid, or acid chloride with the alcohol group of the Formulae (la)-(le) compound.
  • Esterification may also be effected using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and optionally, pyridine, or in the presence of N,N-carbonyldiimidazole with pyridine.
  • Reaction of an acid chloride with the alcohol may be carried out with an acylation catalyst such as 4-DMAP or pyridine.
  • the compounds of Formulae (la)-(le) may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration.
  • Preferred isomers are those with the absolute configuration which produces the compound of Formulae (la)-(le) with the more desirable biological activity.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form.
  • the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.
  • TLC Thin layer chromatography
  • Column chromatography flash chromatography
  • Purification using preparative reversed-phase HPLC chromatography were accomplished using a Gilson 215 system, using a YMC Pro-C18 AS-342 (150 x 20 mm I.D.) column.
  • the mobile phase used was a mixture of H 2 O (A) and MeCN (B).
  • the water may be mixed with 0.1% TFA.
  • a typical gradient is described below:
  • the reaction mixture was then slowly poured into vigorously stirred ice-water (200 mL) and the aqueous layer was extracted with CH 2 CI 2 . The combined organic layers were washed with water, brine, dried (Na 2 SO ), filtered, and concentrated to dryness under vacuum.
  • the resulting crude product was purified by silica gel flash chromatography (gradient of 10-40% ethyl acetate/hexanes) to give 4.2 g (80%) of the title compound.
  • Step 3 Preparation of methyl (2S)-2-f(1 S)-5-hvdroxy-2.3-dihvdro-1H-inden-1- yllpropanoate and methyl (2R)-2-r(1 R)-5-hvdroxy-2.3-dihvdro-1 -inden-1 -yllpropanoate
  • the combined organic layers were washed with HCI (1 L, 1N aqueous solution) and stirred with NaOH (1 L, 1 N aqueous solution).
  • the organic layer was extracted with NaOH (2 x 0.5 L, 1N aqueous solution).
  • the combined aqueous layer was washed with CH 2 CI 2 (2 x 250 mL), and acidified (pH 2.0-3.0) by a slow addition of HCI (37% aqueous solution) maintaining the temperature below 15°C.
  • the acidic mixture was extracted with CH 2 CI 2 (2 x 1.5 L).
  • the combined organic phases were washed with water (2 x 0.5 L) until pH 5.0-6.0 and brine, dried over Na 2 SO 4 , filtered, and then concentrated under reduced pressure.
  • the suspension was cooled to 0°C, then filtered, and the solids were washed with 500 mL acetone. After drying under suction, a sample analyzed by HPLC showed 95% e.e. The recrystallization process was repeated as above using 6.7 L acetone. HPLC analysis showed 99% e.e. After drying under suction, 192 g salt was obtained.
  • the salt was suspended in 2L EtOAc and 1 L of 1N HCI solution and shaken in a separatory funnel, whereupon the salt dissolved. The organic layer was separated, washed with 1N HCI (500 mL), water (2 x 300 mL), and brine, then dried over Na 2 SO 4 .
  • reaction mixture was stirred at 60°C (internal temperature) for 1 h.
  • the reaction was analyzed by TLC after a 1N aqueous hydrochloric acid work- up. After the reaction was completed, it was cooled in an ice-water bath followed by slow addition of 3 L of 1 N hydrochloric acid solution. The pot temperature was kept below 20°C.
  • the mixture was then extracted with 1L ethyl acetate. The organic layer was washed with water until pH 6.0-7.0, then saturated sodium chloride solution, and dried over sodium sulfate.
  • the mixture was poured into 10 mL water, acidified with 1N hydrochloric acid to pH 5, and extracted with (20 mL x 3) ethyl acetate.
  • the combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure, leaving an oil.
  • the crude material was purified by flash chromatography with 10% to 20% ethyl acetate in hexanes to afford 100 mg (53%) of the title compound.
  • Examples 6-11 were prepared by the method exemplified in Reaction Scheme 5.
  • Examples 12 and 13 were prepared by the method exemplified in Reaction Scheme 6.
  • Step 5 Preparation of ethyl difluoro(5-r2-(5-methyl-2-phenyl-1,3-oxazol-4- yl)ethoxyl-2,3-dihvdro-1r7-inden-1-yl)acetate
  • Step 6 Preparation of methyl (2S)-2-IT1 SV5-hvdroxy-3.3-dimethyl-2,3-dihvdro-1H- inden-1-yllbutanoate and methyl (2ffl-2-f(1f?)-5-hvdroxy-3.3-dimethyl-2.3-dihvdro-1r/- inden-1 -yllbutanoate
  • reaction mixture was then diluted with ethyl ether and washed one time with saturated, aqueous sodium bicarbonate.
  • aqueous wash was separated and then extracted with ether.
  • the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
  • the crude residue was purified by column chromatography (30% ethyl acetate in hexane) to provide the desired product (130 mg, 64%).
  • Step 1 5-r2-(5-methyl-2-phenyl-1 ,3-oxazol-4-yl)ethoxy1-1-indanone
  • Step 3 (2-methyl-5-r2-(5-methyl-2-phenyl-1 ,3-oxazol-4-yl)ethoxyl-2,3-dihvdro-1 H- inden-1-yllacetic acid
  • Example 28-44 were prepared by the methods exemplified in Reaction Scheme 10, parts 1 and 2.
  • the obtained white solid was then dissolved in acetic anhydride (42 mL) and toluene (12 mL) solution. The reaction was heated at 50°C for 2 h. The solvent was then removed under reduced pressure. The solid was washed with hot hexane (3 x 50 mL) and dried under vacuum. The product (5.5 g, 20.5 mmol, 76%>) was obtained as a white solid.
  • Step 2 Preparation of r2-(4-Chloro-phenyl)-5-phenethyl-oxazol-4-v ⁇ -acetic acid methyl ester
  • Step 4 Preparation of (1S)-(5-(2-r2-(4-chlorophenyl)-5-phenyl-5-phenethyl- oxazole-4-vn-ethoxy)-indan-1 -yl)-acetic acid
  • R' (C r C 6 )alkyl
  • Step 4 Preparation of ethyl ((1S)-5- ⁇ 2-r5-methyl-2-(6-phenyl-3-pyridinyl)-1.3- oxazol-4-yllethoxy)-2,3-dihvdro-1r/-inden-1-yl)acetat.e
  • Step 5 Preparation of ((1 S)-5-(2-f5-methyl-2-(6-phenyl-3-pyridinvn-1.3-oxazol-4- yllethoxy)-2,3-dihvdro-1H-inden-1-yl)acetic acid
  • Step 1 Methyl (2SV2-((1S 5-(2-r5-methyl-2-(6-phenyl-3-pyridinyl)-1.3-oxazol-4- yllethoxy ⁇ -2,3-dihvdro-1 H-inden-1 -vDpropanoate
  • Step 2 (2S)-2-((1 S)-5-(2-r5-methyl-2-(6-phenyl-3-pyridinvn-1.3-oxazol-4- yllethoxy)-2.3-dihydro-1 H-inden-1 -vQpropanoic acid
  • Step 2 Preparation of methyl (2-amino-5-methyl-1 ,3-thiazol-4-yl)acetate
  • Step 4 Preparation of tert-butyl 4-(2-hvdroxyethyl)-5-methyl-1,3-thiazol-2- ylcarbamate
  • This phosphine oxide adduct was then treated with 1N HCI (10 mL) in THF (10 mL) for 18 h.
  • the THF was removed under reduced pressure, and the remaining aqueous solution was washed with Et 2 O (3 x 50 mL).
  • the aqueous layer was basified using a saturated solution of NaHCO 3 and the product extracted with CH 2 CI 2 (3 x 100 mL).
  • the ether and CH 2 CI 2 layers were combined, dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure.
  • the residue was purified by silica gel flash chromatography (6:4 hexanes/EtOAc to 4:1 EtOAc/MeOH) to yield the product (384 mg, 56%) as a yellowish oil.
  • Example 82 Using the methods described above for Example 80, Example 81, and Intermediate I, and the appropriate acyl halide, sulfonyl chloride, chloroformate, or dicarbonate as starting materials, the compounds of Examples 82-104 were prepared and characterized. In some instances, a catalytic amount of DMAP was added to increase the rate of reaction. The products were purified by silica gel chromatography or preparative HPLC when necessary. [325] Example 82
  • the organic layer was washed successively with 1 N sodium bicarbonate, 1 N sodium sulfite, and brine.
  • the organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the bromoketal as a colorless liquid, which was immediately taken to the next step.
  • Step 1 Preparation of 4-(2-frferf-butyl(diphenvDsilylloxyfethyl)-5-methyl-1H- imidazole
  • Step 2 Preparation of 4-(2 r.e/f-butylfdiphenyl)silylloxy)ethv ⁇ -5-methyl-1-trityl-1 - imidazole
  • Step 3 Preparation of 4-(2- ⁇ r-e/f-butyl(diphenvnsilylloxy)ethyl)-2-iodo-5-methyl-1- trityl-1 /-/-imidazole
  • Step 1 Preparation of ethyl fM S)-5-r2-(2-iodo-5-methyl-1-trityl-1H-imidazol-4- yl)ethoxyl-2,3-dihydro-1H-inden-1-yl>acetate
  • Step 2 Preparation of ethyl ((1 S)-5-r2-(2-iodo-5-methyl-1 H-imidazol-4-v ⁇ ethoxyl- 2,3-dihvdro-1H-inden-1-yl ⁇ acetate
  • Step 2 Preparation of 5-f2-(f.er-butyl(diphenyl)silvnoxy>ethyl)-2-iodo-1.4-dimethyl- 1H-imidazole and 4-(2- ⁇ fferf-butyl(diphenyl)silvnoxylethyl)-2-iodo-1.5-dimethyl-1H- imidazole.
  • Step 3 Preparation of 4-(2-(r.er/-butyl(diphenvDsilv ⁇ o ⁇ y ⁇ ethv ⁇ -1 ,5-dimethyl-2- phenyl-1H-imidazole (Isomer A) and 5-(2- ⁇ rferf-butyl(diphenyl)silv ⁇ oxy)ethylV1 ,4-dimethyl- 2-phenyl-1H-imidazole (Isomer B)
  • Methyl 1-pentyl-1 H-imidazole 5-carboxylate (1) MS (electrospray) 197.2 (M+H) + , 1 H NMR (CDCI 3 ): ⁇ 0.88 (t, 3H), 1.30 (m, 4H), 1.78 (m, 2H), 3.85 (s, 3H), 4.30 (t, 2H), 7.74 (s, 1 H), 7.78 (s, 1H).
  • Methyl 1-pentyl-1 H-imidazole 4-carboxylate (2) MS (electrospray) 197.1 (M+H) + , 1 H NMR (CDCI 3 ) ⁇ 0.89 (t, 3H), 1.31 (m, 4H), 1.81 (m, 2H), 3.89 (s, 3H), 3.96 (t, 2H), 7.62 (s, 1H), 7.71 (s, 1H).
  • Solvents were removed under vacuum, and the residue was dissolved in EtOH/water (1:1, 2 mL) and treated with LiOH (0.016 mg, 0.4 mmol). The solution was heated at 50°C for 12 h. Solvents were evaporated under vacuum, and the residue was dissolved in water and adjusted the pH to 5 with 1N HCI. Solvents were evaporated and the residue was dissolved in acetonitrile and purified by HPLC to obtain the desired product in 15% yield (5 mg, 0.01 mmol).
  • Step 1 Preparation of methyl 3-r(4-bromobenzoyl)amino1-4-oxopentanoate
  • the reaction mixture was then diluted with dichloromethane (500 mL) and washed with 1N HCI (500 mL), brine (500 mL), and dried over Na 2 SO 4 .
  • the resultant amide product (19.3 g, 95%), a white solid, was obtained after solvent removal and drying under vacuum. It was then dissolved in pyridine (50 mL) and DMAP (36 g) was added. Acetic anhydride (56 mL) was added slowly and then the reaction was heated at 90°C for 2 h. The cooled solution was poured into 200 mL ice water and extracted with 800 mL ethyl acetate. The organic layer was washed with 2N HCI (3 x 200 mL) and sat. sodium bicarbonate solution (3 x 200 mL), dried over MgSO , and concentrated to afford the title compound as a white solid (13.2 g, 68%).
  • Step 2 Preparation of methyl 3-r(4-bromobenzovQ(methyl)aminol-4- oxopentanoate
  • Step 3 Preparation of methyl r2-(4-bromophenvD-1.4-dimethyl-1H-imidazol-5- yllacetate
  • Step 4 Preparation of 2-

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Abstract

L'invention concerne de nouveaux dérivés d'acide carboxylique d'indane, de dihydrobenzofurane et de tétrahydronaphthalène utilisés dans le traitement de maladies telles que le diabète, les troubles associés au diabète, l'obésité, l'hyperlipidémie, et les maladies cardiovasculaires. L'invention concerne également des intermédiaires utilisés dans la préparation desdits dérivés carboxyliques, ainsi que des méthodes de préparation de ceux-ci.
PCT/US2003/023342 2002-07-26 2003-07-25 Derives d'acide carboxylique d'indane, de dihydrobenzofurane et de tetrahydronaphthalene et leurs utilisations comme antidiabetiques WO2004011446A1 (fr)

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WO2004080943A1 (fr) * 2003-03-11 2004-09-23 Ono Pharmaceutical Co., Ltd. Procede permettant d'ajouter du charbon actif dans la purification d'eau et procede de purification d'eau
WO2007002563A1 (fr) * 2005-06-27 2007-01-04 Exelixis, Inc. Régulateurs de lxr de type imidazole
WO2007114213A1 (fr) 2006-03-30 2007-10-11 Asahi Kasei Pharma Corporation Dérivé cyclique bicyclique substitué et son utilisation
WO2008006052A2 (fr) * 2006-07-07 2008-01-10 Govek Steven P Inhibiteurs de pde4 à base de composés d'hétéroaryle bicyclique
US7820837B2 (en) 2003-05-30 2010-10-26 Takeda Pharmaceutical Company Limited Condensed ring compound
US7998995B2 (en) 2006-12-08 2011-08-16 Exelixis Patent Company Llc LXR and FXR modulators
JP2012506386A (ja) * 2008-10-21 2012-03-15 メタボレックス， インコーポレイテッド アリールｇｐｒ１２０受容体アゴニストおよびその使用
WO2012046869A1 (fr) 2010-10-08 2012-04-12 持田製薬株式会社 Dérivé d'amide cyclique
CN102648184A (zh) * 2009-05-28 2012-08-22 埃克塞利希斯专利有限责任公司 Lxr调节剂
WO2012147518A1 (fr) 2011-04-27 2012-11-01 持田製薬株式会社 Nouveau dérivé de 1-oxyde de 3-hydroxyisothiazole
WO2012147516A1 (fr) 2011-04-28 2012-11-01 持田製薬株式会社 Dérivé d'amide cyclique
US8334314B2 (en) 2008-04-28 2012-12-18 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
US8476287B2 (en) 2009-12-25 2013-07-02 Mochida Pharmaceutical Co., Ltd. 3-hydroxy-5-arylisothiazole derivative
CN101248049B (zh) * 2005-06-27 2013-08-28 埃克塞利希斯专利有限责任公司 咪唑类lxr调节剂
WO2015097713A1 (fr) 2013-11-14 2015-07-02 Cadila Healthcare Limited Nouveaux composés hétérocycliques
WO2018102399A1 (fr) * 2016-12-02 2018-06-07 T3D Therapeutics, Inc. Procédés d'administration de dose pour traiter ou prévenir une déficience cognitive à l'aide de dérivés d'acide acétique d'indane
CN114560775A (zh) * 2022-03-17 2022-05-31 绵阳师范学院 (r,s)-7-氟-1,1,3-三甲基-2,3-二氢-1h-茚-4-胺的制备方法

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WO2002018355A1 (fr) * 2000-08-23 2002-03-07 Eli Lilly And Company Dérivés d'acide oxazolyl-aryloxyacétique et leur utilisation comme agonistes des ppar
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WO2004080943A1 (fr) * 2003-03-11 2004-09-23 Ono Pharmaceutical Co., Ltd. Procede permettant d'ajouter du charbon actif dans la purification d'eau et procede de purification d'eau
US7820837B2 (en) 2003-05-30 2010-10-26 Takeda Pharmaceutical Company Limited Condensed ring compound
CN101248049B (zh) * 2005-06-27 2013-08-28 埃克塞利希斯专利有限责任公司 咪唑类lxr调节剂
JP2008543971A (ja) * 2005-06-27 2008-12-04 エグゼリクシス， インコーポレイテッド イミダゾールに基づくｌｘｒモジュレーター
US8703805B2 (en) 2005-06-27 2014-04-22 Exelixis Patent Company Llc Modulators of LXR
US9000022B2 (en) 2005-06-27 2015-04-07 Exelixis Patent Company Llc Imidazole based LXR modulators
US8569352B2 (en) 2005-06-27 2013-10-29 Exelixis Patent Company Llc Imidazole based LXR modulators
WO2007002563A1 (fr) * 2005-06-27 2007-01-04 Exelixis, Inc. Régulateurs de lxr de type imidazole
WO2007114213A1 (fr) 2006-03-30 2007-10-11 Asahi Kasei Pharma Corporation Dérivé cyclique bicyclique substitué et son utilisation
WO2008006052A2 (fr) * 2006-07-07 2008-01-10 Govek Steven P Inhibiteurs de pde4 à base de composés d'hétéroaryle bicyclique
WO2008006052A3 (fr) * 2006-07-07 2008-11-20 Steven P Govek Inhibiteurs de pde4 à base de composés d'hétéroaryle bicyclique
US7998995B2 (en) 2006-12-08 2011-08-16 Exelixis Patent Company Llc LXR and FXR modulators
US8772327B2 (en) 2008-04-28 2014-07-08 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
US8334314B2 (en) 2008-04-28 2012-12-18 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
JP2012506386A (ja) * 2008-10-21 2012-03-15 メタボレックス， インコーポレイテッド アリールｇｐｒ１２０受容体アゴニストおよびその使用
CN102648184B (zh) * 2009-05-28 2015-09-30 埃克塞利希斯专利有限责任公司 Lxr调节剂
CN102648184A (zh) * 2009-05-28 2012-08-22 埃克塞利希斯专利有限责任公司 Lxr调节剂
US8476287B2 (en) 2009-12-25 2013-07-02 Mochida Pharmaceutical Co., Ltd. 3-hydroxy-5-arylisothiazole derivative
US9040525B2 (en) 2010-10-08 2015-05-26 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
WO2012046869A1 (fr) 2010-10-08 2012-04-12 持田製薬株式会社 Dérivé d'amide cyclique
US8557766B2 (en) 2011-04-27 2013-10-15 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
US8765752B2 (en) 2011-04-27 2014-07-01 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
US8629102B2 (en) 2011-04-27 2014-01-14 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
WO2012147518A1 (fr) 2011-04-27 2012-11-01 持田製薬株式会社 Nouveau dérivé de 1-oxyde de 3-hydroxyisothiazole
WO2012147516A1 (fr) 2011-04-28 2012-11-01 持田製薬株式会社 Dérivé d'amide cyclique
US9072758B2 (en) 2011-04-28 2015-07-07 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
WO2015097713A1 (fr) 2013-11-14 2015-07-02 Cadila Healthcare Limited Nouveaux composés hétérocycliques
US10011609B2 (en) 2013-11-14 2018-07-03 Cadila Healthcare Limited Heterocyclic compounds
US10246470B2 (en) 2013-11-14 2019-04-02 Cadila Healthcare Limited Heterocyclic compounds
WO2018102399A1 (fr) * 2016-12-02 2018-06-07 T3D Therapeutics, Inc. Procédés d'administration de dose pour traiter ou prévenir une déficience cognitive à l'aide de dérivés d'acide acétique d'indane
CN114560775A (zh) * 2022-03-17 2022-05-31 绵阳师范学院 (r,s)-7-氟-1,1,3-三甲基-2,3-二氢-1h-茚-4-胺的制备方法
CN114560775B (zh) * 2022-03-17 2023-08-22 绵阳师范学院 (r,s)-7-氟-1,1,3-三甲基-2,3-二氢-1h-茚-4-胺的制备方法

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